Lysine-Specific Demethylase 1 (LSD1) Inhibitors: Peptides as an Emerging Class of Therapeutics

Abstract

Aberrant expression of the epigenetic regulator lysine-specific demethylase 1 (LSD1) has been associated with the incidence of many diseases, particularly cancer, and it has evolved as a promising epigenetic target over the years for treatment. The advent of LSD1 inhibitor-based clinical utility began with tranylcypromine, and it is now considered an inevitable scaffold in the search for other irreversible novel LSD1 inhibitors (IMG-7289 or bomedemstat, ORY1001 or iadademstat, ORY-2001 or vafidemstat, GSK2879552, and INCB059872). Moreover, numerous reversible inhibitors for LSD1 have been reported in the literature, including clinical candidates CC-90011 (pulrodemstat) and SP-2577 (seclidemstat). There is parallel mining for peptide-based LSD1 inhibitors, which exploits the opportunities in the LSD1 substrate binding pocket. This Review highlights the research progress on reversible and irreversible peptide/peptidederived LSD1 inhibitors. For the first time, we comprehensively organized the peptide-based LSD1 inhibitors from the design strategy. Peptide inhibitors of LSD1 are classified as H3 peptide and SNAIL1 peptide derivatives, along with miscellaneous peptides that include naturally occurring LSD1 inhibitors.

Anticancer Drugs of Lysine Specific Histone Demethylase-1 (LSD1) Display Variable Inhibition on Nucleosome Substrates

“…An exploration of new druggable spaces that target LSD1’s structural and context specific interaction network is highly relevant in the design of effective inhibitors and anticancer therapies. − A series of impressive studies that interrogate small molecule compounds as inhibitors of LSD1 catalytic activity are available in the literature, , yet it is unclear whether some of these small molecule compounds serve as potent LSD1 inhibitors on nucleosome substrates. Inhibitor activity studies on nucleosome substrates offer insight into the development of more selective LSD1-based drug and help to distinguish whether the drug functions as an LSD1 inhibitor on nucleosomes, a protein–protein disruptor, and/or an inducer of cell differentiation.…”

“…Inhibitor activity studies on nucleosome substrates offer insight into the development of more selective LSD1-based drug and help to distinguish whether the drug functions as an LSD1 inhibitor on nucleosomes, a protein–protein disruptor, and/or an inducer of cell differentiation. This is especially relevant for established inhibitors of LSD1 that appear to exhibit poor selectivity, potency, efficacy, and off-target toxicity, all of which may complicate and limit the interrogation of LSD1 as a viable therapeutic strategy. , Nonetheless, several inhibitors have entered clinical trials, and intensive pharmacological efforts have focused on the treatment of acute myeloid leukemia (AML), myelodysplastic syndrome, small cell lung cancer (SCLC), and prostate cancer. − ,, …”